title: Refining the phenotype of alpha-1a Tubulin (TUBA1A) mutation in patients with classical lissencephaly.
abstract: Mutations in the alpha-1a Tubulin (TUBA1A) gene have recently been found to cause cortical malformations resemblant of classical lissencephaly but with a specific combination of features. To date, TUBA1A mutations have been described in five patients and three foetuses. Our aims were to establish how common TUBA1A mutations are in patients with lissencephaly and to contribute to defining the phenotype associated with TUBA1A mutation. We performed mutation analysis in the TUBA1A gene in 46 patients with classical lissencephaly. In 44 of the patients, mutations in the LIS1 and/or DCX genes had previously been excluded; in 2 patients, mutation analysis was only performed in TUBA1A based on magnetic resonance imaging (MRI) findings. We identified three new mutations and one recurrent mutation in five patients with variable patterns of lissencephaly on brain MRI. Four of the five patients had congenital microcephaly, and all had dysgenesis of the corpus callosum and cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. We estimate the frequency of mutation in TUBA1A gene in patients with classical lissencephaly to be approximately 4%, and although not as common as mutations in the LIS1 or DCX genes, mutation analysis in TUBA1A should be included in the molecular genetic diagnosis of classical lissencephaly, particularly in patients with the combination of features highlighted in this paper.
authors.affiliation: Institute for Human Genetics and Anthropology, Albert-Ludwigs University of Freiburg, Freiburg, Germany. deborah.morris-rosendahl@uniklinik-freiburg.de
authors.forename: D J
authors.initials: DJ
authors.lastname: Morris-Rosendahl
authors.forename: J
authors.initials: J
authors.lastname: Najm
authors.forename: A M A
authors.initials: AM
authors.lastname: Lachmeijer
authors.forename: L
authors.initials: L
authors.lastname: Sztriha
authors.forename: M
authors.initials: M
authors.lastname: Martins
authors.forename: A
authors.initials: A
authors.lastname: Kuechler
authors.forename: V
authors.initials: V
authors.lastname: Haug
authors.forename: C
authors.initials: C
authors.lastname: Zeschnigk
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.forename: M
authors.initials: M
authors.lastname: Santos
authors.forename: C
authors.initials: C
authors.lastname: Vasconcelos
authors.forename: H
authors.initials: H
authors.lastname: Omran
authors.forename: U
authors.initials: U
authors.lastname: Kraus
authors.forename: M S
authors.initials: MS
authors.lastname: Van der Knaap
authors.forename: G
authors.initials: G
authors.lastname: Schuierer
authors.forename: K
authors.initials: K
authors.lastname: Kutsche
authors.forename: G
authors.initials: G
authors.lastname: Uyanik
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D006801:Humans; D054082:Lissencephaly / Q000235:genetics* / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D014404:Tubulin / Q000235:genetics*
chemical_list: C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C533522:TUBA1A protein, human; D014404:Tubulin; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human